The Oxygen carrying function of our blood depends on the structure of hemoglobin packed in red blood cells. Changes in the structure of hemoglobin often result in aberrations of the functional behavior and pathological conditions such as sickle cell anemia, hemolysis and cyanosis among others. This proposal is directed towards the key area of understanding the functional behavior of hemoglobin on a molecular basis. An attempt is being made to study the ligand combination and dissociation processes in terms of the specific structural features of the heme pocket, i.e., the role of the structural features of the heme pocket on the proximal side of the heme, on the distal side of heme, and the porphyrin related structural features. The human hemoglobin mutants (Hb M Iwate alpha F3 (87) (His yields Tyr), Hb M Hyde Park beta F8 (92) (His yields Tyr) and other M hemoglobins) selected for the present study are all of clinical significance and provide the unique opportunity to study the role of the proximal base on the functional behavior of hemoglobin. In addition to this, studies will also be made on normal hemoglobin and some model compounds. The project offers the prospect of understanding the differences encountered in the behavior of O2, CO and NO towards normal human hemoglobin. The project will also provide kinetic data on the partially saturated intermediates and the role these species may play in determining the functional and physiological behavior of normal hemoglobin as well as in determining the reaction mechanism.